Submissions for variant NM_001035.3(RYR2):c.12533A>G (p.Asn4178Ser)

dbSNP: rs794728787

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000182820	SCV000235206	likely pathogenic	not provided	2016-09-01	criteria provided, single submitter	clinical testing	The N4178S likely pathogenic variant in the RYR2 gene was reported as a novel mutation" in three of 155 unrelated probands with either a confirmed clinical diagnosis of CPVT or an initial diagnosis of exercise-induced LQTS but with QTc <480 ms and subsequent negative LQTS genetic testing; specific clinical information for affected probands was not provided (Medeiros-Domingo et al., 2009). Subsequently, N4178S was identified in a Japanese individual with CPVT and was absent from both clinically-unaffected parents (Kawamura et al., 2013; Ohno et al., 2015). In addition, the N4178S variant has been identified independently in two other individuals referred for CPVT testing for at GeneDx; familial segregation data available for one of these individuals was consistent with de novo inheritance. Moreover, N4178S was not observed in approximately 6,200 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. The N4178S variant is a conservative amino acid substitution, which is not likely to impact secondary protein structure as these residues share similar properties. Nevertheless, this substitution occurs at a position that is conserved across species, and in silico analysis predicts this variant is probably damaging to the protein structure/function. Furthermore, the N4178S variant is located in one of the three hot-spot regions of the RYR2 gene, where the majority of pathogenic missense variants occur (Medeiros-Domingo et al., 2009). Finally, a missense variant at the same residue (N4178Y) has been reported in the Human Gene Mutation Database in association with CPVT (Stenson et al., 2014); however, the pathogenicity of this variant has not been definitely determined.Therefore, this variant is likely pathogenic."
Labcorp Genetics (formerly Invitae), Labcorp	RCV001248790	SCV001415164	pathogenic	Catecholaminergic polymorphic ventricular tachycardia 1	2023-08-03	criteria provided, single submitter	clinical testing	This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with clinical features of catecholaminergic polymorphic ventricular tachycardia (PMID: 19926015, 26114861; Invitae). In at least one individual the variant was observed to be de novo. ClinVar contains an entry for this variant (Variation ID: 201334). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt RYR2 protein function. This variant disrupts the p.Asn4178 amino acid residue in RYR2. Other variant(s) that disrupt this residue have been observed in individuals with RYR2-related conditions (PMID: 19398665), which suggests that this may be a clinically significant amino acid residue. For these reasons, this variant has been classified as Pathogenic. This sequence change replaces asparagine, which is neutral and polar, with serine, which is neutral and polar, at codon 4178 of the RYR2 protein (p.Asn4178Ser).
Center For Human Genetics And Laboratory Diagnostics, Dr. Klein, Dr. Rost And Colleagues	RCV001248790	SCV001422300	pathogenic	Catecholaminergic polymorphic ventricular tachycardia 1	2020-01-31	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV002415777	SCV002676509	likely pathogenic	Cardiovascular phenotype	2016-07-25	criteria provided, single submitter	clinical testing	The p.N4178S variant (also known as c.12533A>G), located in coding exon 90 of the RYR2 gene, results from an A to G substitution at nucleotide position 12533. The asparagine at codon 4178 is replaced by serine, an amino acid with highly similar properties. In a study of RYR2 clinical genetic testing, this alteration was reported in three individuals with catecholaminergic polymorphic ventricular tachycardia (CPVT) phenotype or exertional syncope (Medeiros-Domingo A et al. J Am Coll Cardiol. 2009;54:2065-74). In a different study, this variant was detected as likely de novo in a patient with CPVT (Ohno S et al. PLoS ONE. 2015;10:e0131517). Additionally, another alteration involving the same amino acid, p.N4178Y (c.12532A>T), was described in a CPVT cohort (Hayashi M et al. Circulation. 2009;119(18):2426-34). This p.N4178S variant was previously reported in the SNPDatabase as rs794728787, but was absent from population-based cohorts in the NHLBI Exome Sequencing Project (ESP) and 1000 Genomes Project databases. In the ESP, this variant was not observed in 6153 samples (12306 alleles) with coverage at this position. This amino acid position is highly conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Based on the majority of available evidence to date, this variant is likely to be pathogenic.